1. Technical Field
This invention relates to a topical analgesic composition; in particular, the invention concerns a synergistic combination of a topical anesthetic and wound barrier forming agent capable of providing extended analgesia of ‘significant open wounds’—that being, for example, a laceration, surgical incision, abrasion, ulcer or burn, but not being a minor cut, scratch, sting, burn or abrasion.
2. Description of the Background Art
Pain from an open wound (e.g. laceration, surgical incision, ulcer or burn) is initiated by a stimulation of traumatized nerve fibers and is intensified by a local inflammatory response that occurs over ensuing 24-48 hours and results in local tissue swelling and edema. Pain from an open wound is also further intensified and prolonged by a sensitization reaction of higher nerve function which also occurs over ensuing hours and days, and may lead to lower pain thresholds and prolonged hypersensitivity of surrounding tissues. Such wounds are usually treated by closing or sealing the wound, such as by suturing, adhesive plastering, bandaging or other practice. Closing the wound stops bleeding, protects traumatized tissues and nerve fibers from dehydration, ongoing environmental exposure, risk of infection and ongoing painful stimulation. Pain therefore abates as the inflammatory response and tissue edema subsides.
Where available, pain related to such wounds is managed using systemic analgesia (such as oral, IM or IV opioids or non-steroidal anti-inflammatory agents) and/or injected local anesthetic agents. In this situation, injected local anesthetic agents are generally used for short term wound anesthesia prior to debriding, suturing or otherwise closing or treating the wound. They may also be indicated as providing prolonged pain relief during and following surgical procedures in which the wound is generally closed. Local anesthetic agents generally act by blocking nerve conduction, thereby reducing or eliminating pain sensation for the duration of their action, which is generally in the order of 30 minutes to several hours depending on the agent and method of administration. Prolonged analgesia may be achieved using injections of anesthetic agents having a long duration of action, such as bupivacaine (duration of action 6-8 hours following injection), or by using repeated or continuous subcutaneous injection or infusion, or by combining an anesthetic agent with a special implantable or injectable delivery vehicle that results in slow-release diffusion (US Patent Application No. 2003/0185873 A1).
Some local anesthetic agents may be applied topically; however, they have reduced efficacy and potency when used with this method of application. They typically only provide anesthesia for 30 to 60 minutes in open wound situations. This may be adequate to anaesthetize the wound in preparation for debriding, cleaning, suturing etc; however, they are rarely indicated for analgesia of acute and significant open wounds other than for this short term application. Slow-release vehicles may prolong the duration of topical anesthesia to a certain extent, but not usually greater than a doubling of the 30 minute to 60 minute analgesic period.
In many cases, however, the management strategies for closing acute and significant open wounds are impractical, unaffordable or unavailable and wounds are therefore left open to heal by secondary intention. This applies to a very large number of acute traumatic and/or surgically induced wounds, particularly in animals. Examples include:
1. Wounds in animals, including traumatic wounds and/or those caused by husbandry procedures such as branding, castration, dehorning, tail docking and mulesing.
2. Wounds in mass human trauma situations, such as earthquakes, floods and wars.
3. Wounds that occur in remote locations and Third World countries where medical attention may be limited or unavailable.
Where an acute and significant laceration and/or traumatic wound remains open and/or otherwise untreated for a prolonged period, bleeding continues unless or until natural clotting occurs. In addition, ongoing exposure of traumatized tissues results in increased risk of contamination and/or infection as well as ongoing painful stimulation of traumatized nerve fibers. This may be exacerbated by the local and systemic inflammatory and immune responses that occur when tissue and blood components are exposed to foreign (external) materials or surfaces. Inflammatory exudates contain many factors that cause and/or exacerbate pain. In this situation, pain may eventually abate as a natural ‘covering’ or ‘seal’ forms over the wound due to clotting and crusting of blood and inflammatory exudates. This serves to protect raw nerve endings from exposure to the environment. However, pain may continue or intensify during the healing process if such a seal dries out and/or becomes infected and cracks open or becomes ulcerated, thereby leaving raw nerve tissue exposed to the environment again.
Burn injuries constitute a prominent example of a significant open wound that cannot be closed by suturing. Where pain from burn injury is significant it is usually managed with systemic analgesia, however burns are typically also ‘sealed’, ‘covered’ or ‘closed’ by the application of ‘barrier’ formulations (which usually consisting of thick oil or cream based topical applications) and/or bandaging, or by the application of films, artificial ‘skins’ or skin grafts. Such ‘barrier preparations’ act to provide an immediate cover over the wound, which prevents heat and water loss from the wound surface, and act as a barrier against bacterial contamination, thus aiding the healing process and reducing morbidity. They are also known to provide a measure of analgesia. (Bose B. Burn. Wound Dressing with Human Amniotic Membrane. Annals of the Royal College of Surgeons of England. 61(6):444-7, 1979 Nov. 2, Weiss R A. Goldman M P Interpenetrating Polymer Network Wound Dressing Versus Petrolatum Following Facial CO2 Laser Resurfacing: A Bilateral Comparison. Dermatologic Surgery. 27(5):449-51, 2001 May). However, they are not potent at providing wound anesthesia in the acute situation (in which nerve endings are stimulated and instigate pain sensitization and wound hyperalgesia in response to being cut, burned or traumatized), but rather they act to reduce pain in the later stages by placing a moist and constant seal over exposed nerve endings. This protects against drying and ongoing stimulation by interaction with the open environment while wounds re-epithelialize and nerve fibers regenerate. Despite being well recognized for this particular open wound situation, barrier formulations are not generally indicated for other open wounds such as those due to trauma and lacerations. This is principally because: A) barrier formulations generally cannot adhere adequately to wounds that are actively bleeding; and/or B) alternative treatments such as suturing, adhesive bandaging or otherwise closing the wound are available or preferred.
Significant cuts, abrasions and lacerations that remain open and/or bleeding due to impracticality, lack of availability or affordability of preferred management strategies (such as primary closure and/or systemic analgesia) at present therefore receive little to no treatment—either via analgesic administration or wound barrier application.
It is the present inventors' novel contention that topical anesthetic agents can be used effectively to manage and reduce pain in these situations if combined with carriers having the following characteristics: 1) that they promote and/or prolong anesthetic absorption into an open wound; and 2) that they provide a long-lasting barrier (seal) over the open wound. It is the present inventors' contention that the early anesthetic effects of topical anesthetic agents can work synergistically with analgesic effects of barrier formulations to provide extended wound analgesia for all such indications.
It is important to note that until now analgesia from wound pain has not even been considered in most of these situations. Where it has been considered, topical anesthesia has been considered too slow acting, of too short a duration and/or of ineffective potency to provide a suitably effective sole mechanism of analgesia for this indication. Similarly, had it previously been considered, barrier treatments would not have been felt to be practical or effective at providing significant analgesia in such situations due to their inability to adhere to actively bleeding/weeping wounds, or the potential to interfere with the absorption of anesthetic agents. Nevertheless, the present inventors had the novel idea that synergistic interaction between the early anesthetic effects of topical anesthesia and the later analgesic effects of wound barrier formulations had the potential to be harnessed to provide a mechanism of effecting simple, effective and prolonged analgesia of significant wounds that were likely to remain open or otherwise untreated for prolonged periods. This novel combination is not taught by the prior art for at least the reasons given below.
Many/most of the known topical anesthetic compositions are designed for use on intact skin and therefore are not suitable for this indication. Examples include RESOLVE™, EMLA™ and AMETOPP™. These compositions are recommended for anesthesia of skin prior to minor procedures (such as performing needle insertion) or for temporary relief of minor skin irritations (such as minor cuts, stings and grazes). Because the skin acts as a barrier that prevents local anesthetic agents from reaching the subcutaneous nerve fibers on which they act, these compositions contain relatively high anesthetic concentrations compared with injectable compositions (to improve potency) and may contain promoters (skin penetration enhancers) to aid absorption through the skin. Despite this, they require prolonged (30-60 min) contact with the skin to achieve an anesthetic effect. This usually requires covering the anesthetic composition with gauze, wrap or other medical covering, or application of an impregnated patch to maintain prolonged contact. Repeat applications are required to maintain anesthesia longer than 30-60 minutes. Because they are designed for intact skin, most do not contain vasoconstricting agents or agents for forming a wound barrier, which would be considered likely to reduce their potency and duration of effect when used on intact skin. However, several of these factors may combine to increase the risk of high level absorption if the agents are used on significant open wounds, for which they are therefore contra-indicated in many/most situations.
Many other known topical anesthetic formulations are specifically designed for use on mucous membranes, such as in the eyes or mouth. Topical anesthesia is more rapid and efficacious when used on such regions as the structure of skin allows easy penetration and anesthetic agents have more direct access to nerve fibers. Topical anesthetic compositions are therefore frequently used to provide pain relief for lesions and/or procedures in the eyes and mouth. Some commercially available compositions include XYLOCAINE VISCOUS™, and AAA™ mouth and throat spray. However, because of rapid penetration via mucous membranes, there is also a risk of rapid systemic absorption of the anesthetic agents away from the local tissues and into the blood stream. This has the capacity to reduce the duration of the anesthetic effect and to increase the risk of systemic toxicity. Because of this, such compositions usually contain relatively low anesthetic concentrations and/or are not formulated in carriers designed to achieve intrinsic analgesia of significant open wounds due to a barrier effect and are therefore also inappropriate for this indication.
Topical local anesthetic compositions have been trialled and/or recommended for use in small to medium lacerations immediately prior to suturing. Examples of liquid anesthetic compositions that have been trialled and/or recommended for use on small to medium lacerations include TAC (tetracaine, adrenaline and cocaine) and LET (lidocaine, epinephrine and tetracaine), being combinations of high dose anesthetic agents and vasoconstrictors. These compositions have been designed to provide short term anesthesia (usually 30 mins to 1 hour) and control bleeding, which allows the wounds to be cleaned and sutured, avoiding the need for local anesthetic infiltration. Such compositions can be as effective as injected lignocaine at anesthetizing a wound for suturing, particularly on the face and scalp (Stewart A M, Simpson P, Rosenberg N M. Use of topical lidocaine in pediatric laceration repair: A review of topical anesthetics. Ped Emerg Care. 1998; 14:419-423). These compositions contain higher doses of local anesthetic agents to improve potency and anesthetic effect. The risk of systemic absorption is reduced by including a vasoconstrictor, but also by limiting the use of the compositions to wounds below a certain size. Such compositions are generally applied by soaking a gauze in the composition and placing it on the wound, with repeated applications as required.
Sterile gels have been used as carriers for such indications. U.S. Pat. No. 5,563,153 is for an anesthetic composition having GELFOAM™ as a carrier, and U.S. Pat. No. 6,620,852 is for an anesthetic composition having SURGILUBE™ as a carrier. Such compositions, however, have not been designed to provide extended pain relief for wounds that are likely to remain open for prolonged periods and the duration of anesthetic effect on open wound situations is generally limited to ½ to 2 hours without repeat applications.
With regard to U.S. Pat. No. 5,563,153, the anesthetic composition having GELFOAM™ as a carrier is applied as a gelatinous paste (having the consistency of peanut butter) to an open wound and is principally designed to be used prior to repair or suturing the wound “Tackiness” is mentioned as being a desirable characteristic of the carrier; however, this is to prevent the actives running off the wound and into the eyes or mouth where they may exert increased toxicity. Easy removal by saline irrigation is also mentioned. This is so that the gel matrix can be removed once the wound is prepared for suturing. In Example 1 of U.S. Pat. No. 5,563,153, it is mentioned that the gel was applied to a wound and then covered by a gauze, suggesting a lack of intrinsic adhesion to the wound. Furthermore, it is mentioned that the gel appeared to “melt” when it entered the wound and was easily irrigated away. Hence, GELFOAM™ was not intended to provide a long-lasting barrier (seal) over the open wound, nor was it intended to provide a prolonged analgesic effect due to intrinsic characteristics of the gel.
With regard to U.S. Pat. No. 6,620,852, the anesthetic composition has SURGILUBE™ as a carrier and, being free-flowing, is typically applied to an open wound by way of dripping onto the wound or by soaking and covering with a gauze. Again SURGILUBE™ was intended for use on open wounds prior to suturing, rather than for extended pain relief in wounds that are likely to remain open to heal by secondary intention. Hence, SURGILUBE™ was not intended to provide a long-lasting barrier (seal) over the open wound, nor was it intended to provide a prolonged analgesic effect due to intrinsic characteristics of the carrier.
The use of topical anesthesia has also been described for pain relief in patients with significant burns (Jellish W S, Gamelli R L, Furry P A, McGill V L, Fluder E M. Effect of topical local anesthetic application to skin harvest sites for pain management in burn patients undergoing skin-grafting procedures. Ann Surg. 1999 January; 229(1):115-20; Brofeldt B T, Cornwell P, Doherty D, Batra K, Gunther R A. Topical lidocaine in the treatment of partial-thickness burns. J Burn Care Rehabil. 1989 January-February; 10(1):63-8). In this situation, the local anesthetic agents (typically lignocaine or EMLA) are applied as creams or solutions which may be covered with a bandage, plastic wrap or gauze to maintain contact with the wound, and can require regular re-application (every 2 to 4 hours if prolonged analgesia is required).
Although topical anesthesia and barrier treatments have been both described in isolation for the management of different aspects of significant open wounds, it has not been previously described to combine the two to achieve a single composition which is capable of acting as the primary mechanism of achieving extended pain relief in significant open wound situations—particularly traumatic or surgically induced cuts, abrasions or lacerations. One of the reasons this has not previously been described is that the need for such a composition was not considered, as many of these wounds occur in animals in whom pain management has been considered a low priority until recently. However, where a need was recognized, the principal reason that the combination was not described was that it was not intuitive. Topical anesthetics were not considered as an option due to their limited duration of action and potential toxicity. Similarly, barrier formulations were not generally considered an option because they are usually rendered ineffective by their inability to adhere to actively bleeding or weeping surfaces, particularly in the acute situation (the first 24-48 hours). In addition, the potential for synergism in analgesic actions with barrier formulations was either not considered or unrecognized as the majority of barrier formulations hinder or block effective absorption of anesthetic agents into a wound by forming an impenetrable coating on the wound surface, on and around exposed nerve tissue.
However, the present inventors made the discovery that some viscous carriers can provide a dual function, in that they can act to promote and/or prolong anesthetic absorption into an open wound as well as provide an effective wound barrier that outlasts the action of the anesthetic agent. The present inventors discovered that the analgesic action of such barrier compositions has the potential to be dramatically improved and thereby contribute to pain reduction in the early, as well as later stages of the wound pain response. This is due to previously unrecognized synergistic interactions between the local anesthetic agent and carrier/barrier.
Trial work by the present inventors revealed that allodynia and early wound hyperalgesia and pain sensitization were prevented or minimized by nerve blockade due to effective action of a topical anesthetic agent. As expected, this effect was enhanced and prolonged (to about 2 hours) by applying a combination of anesthetic agents, with a vasoconstrictor in a slow release carrier such as a viscous gel. In addition, however, the carrier surprisingly exerted its own intrinsic analgesic effect. This is believed to be due to adhesion to the wound and formation of a wound barrier or ‘seal’ against the environment. In the absence of anesthetic actives this effect became apparent beginning by about 4 hours. Therefore, when used in combination with the anesthetic actives earlier onset, enhanced and prolonged analgesia was achieved due to novel synergistic interactions.
When used in combination with anesthetic actives analgesic effect from the barrier occurred earlier (beginning by 2 hours) than when used alone. It is hypothesized that the absence of wound allodynia, hyperalgesia and sensitization (which occurred as a primary effect of the action of local anesthetic agents) promoted improved potency and earlier onset of analgesia from the wound barrier effect. The analgesic effect of the wound barrier formulation therefore overlapped, enhanced and prolonged the duration of analgesia achieved as a result of the action of the anesthetic actives, and the combined analgesic action exceeded that which may have been anticipated from the actions of either agents alone or in non-synergistic combination.
In addition, a further synergistic effect was achieved due to the enhanced wound healing attributes supplied by such a composition, which had the potential to produce ongoing pain relief by preventing wound crusting, drying and cracking. A final synergistic effect is achieved by the lowered risk of toxicity and enhanced duration of anesthetic effect that is achieved due to the barrier providing controlled release of the anesthetic agent onto the wound.
Trial work by the present inventors also confirmed that toxicity risks of applying topical anesthetic agents to large open wounds are significantly lower than previously thought and remain well below toxic absorption levels despite relatively high dose applications when compared with injected administration. (Karatassas A, Morris R G, Slavotinek A H. The relationship between regional blood flow and absorption of lignocaine. Australian & New Zealand Journal of Surgery. 1993 October; 63(10):766-71; Brofeldt B T, Cornwell P, Doherty D, Batra K, Gunther R A. Topical lidocaine in the treatment of partial-thickness burns. J Burn Care Rehabil. 1989 January-February; 10(1):63-8).
Therefore, the present inventors have discovered novel synergistic interactions that can be harnessed to provide safe and effective topical anesthesia of significant wounds for use in situations where conventional or more intensive or invasive alternatives are unaffordable, impractical or otherwise unavailable.
The novel synergistic combination of topical anesthesia and a wound barrier forming carrier agent has the potential to provide a means of effectively treating pain and improve wound healing in an extremely large number of major open wound situations, both in humans and animals, where previously it was considered that topical anesthesia would have been either too short-lived, too ineffective, or too high a risk of toxicity to be a viable pain management technique and where barrier treatments may otherwise have remained unconsidered.